title: pH-sensitive docetaxel-loaded D-α-tocopheryl polyethylene glycol succinate-poly(β-amino ester) copolymer nanoparticles for overcoming multidrug resistance.
abstract: Multidrug resistance (MDR) is one of the major obstacles to successful chemotherapy. Overexpression of drug efflux transporters such as P-glycoprotein (P-gp) is an important factor responsible for MDR. Herein, a novel copolymer, D-α-tocopheryl polyethylene glycol 1000-block-poly(β-amino ester) (TPGS-b-PBAE, TP), was synthesized for overcoming multidrug resistance by the synergistic effect of the pH-sensitive behavior of PBAE and P-gp inhibiting activity of TPGS. Docetaxel (DTX) was chosen as the model drug. The resulting DTX-loaded nanoparticles were stable at pH 7.4, while they dissociated in a weakly acidic environment (pH 5.5) and released the incorporated DTX quickly. The DTX-loaded TP nanoparticles increased the cell cytotoxicity against both drug-sensitive human ovarian A2780 and drug-resistant A2780/T cells. The IC(50) of DTX-loaded TP against A2780/T cells was 100-fold lower than that of commercial DTX. This was associated with enhanced DTX-induced apoptosis and cell arrest in the G2/M phase. Furthermore, P-gp inhibition assays, including enhancement of the fluorescence intensity of rhodamine 123 and reduction of the intracellular ATP levels, confirmed the P-gp inhibition nature of the TP copolymer. The use of the TP copolymer is a new approach to improve the therapeutic effect of anticancer drugs in MDR tumors.
authors.affiliation: Tongji School of Pharmacy & National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhao
authors.forename: Songwei
authors.initials: S
authors.lastname: Tan
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Guo
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.forename: Min
authors.initials: M
authors.lastname: Chu
authors.forename: Hudan
authors.initials: H
authors.lastname: Liu
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006863:Hydrogen-Ion Concentration; D053758:Nanoparticles / Q000737:chemistry* / Q000378:metabolism; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D043823:Taxoids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D014810:Vitamin E / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D011108:Polymers; D043823:Taxoids; C507253:poly(beta-amino ester); D014810:Vitamin E; D000077143:Docetaxel; D011092:Polyethylene Glycols; C014225:tocophersolan